The present invention refers to a preparation process of the sodium salt of 6[D-(xe2x88x92)xcex1-4-(ethyl-2,3-dioxo-1-piperazinocarbonylamino)phenylacetamido]penicillanic acid, useful as active ingredient in the treatment of pneumonia, peritonitis and blood infection.
Many preparation processes of the sodium salt of penicillanic acids and, in particular of 6[D-(xe2x88x92)xcex1-4-(ethyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetamido]penicillanic acid are already known.
By way of example, mention is made of the processes described in the European Patent Application No. EP 294 789 or in the U.S. Pat. No. 4,112,090. Such processes, when scaled up to industrial level, show considerable drawbacks, especially when they are meant for the production of a sterile sodium salt. For example, when the salification is carried out with sodium 2-ethyl hexanoate, the sodium salt content, determined in the salification product by HPLC, is low because of the large amount of hexanoic acid that forms and remains in the final product as an hardly eliminable residue. Conversely, when the penicillanic acid is salified with a strong base, such as sodium hydroxide or sodium methoxide or sodium ethoxide, the molecule of the acidxe2x80x94due to the highly alkaline mediumxe2x80x94can degrade giving hardly eliminable by-products, if the salt is separated by crystallisation.
These are the reasons why the commercially available sodium salt of 6[D-(xe2x88x92)xcex1-4-(ethyl-2,3-dioxo-1-piperazinocarbonylamino)phenylacetamido]penicillanic acid is now produced by lyophilisation, which procedure does not require acid purification. Therefore, the need for a scalable process of preparation of the sodium salt of 6[D-(xe2x88x92)xcex1-4-(ethyl-2,3-dioxo-1-piperazinocarbonylamino)phenylacetamido] penicillanic acid, in particular in the sterile form is deeply felt.
The Applicant has found that the sodium-salt of 6[D-(xe2x88x92)xcex1-4-(ethyl-2,3-dioxo-1-piperazinocarbonylamino)phenylacetamido]penicillanic acid can be prepared, also industrially, and separated by precipitation from the solution in which it forms, under operating conditions envisaging the use, in the salification, of the acid and bases in the form of solutions, thus obtaining a high-purity final product in high yields.
It is therefore subject of the invention to provide a preparation process of the sodium salt of 6[D-(xe2x88x92)xcex1-4-(ethyl-2,3-dioxo-1-piperazinocarbonylamino)phenylacetamido] penicillanic acid, comprising the reaction of a solution of the 6[D-(xe2x88x92)xcex1-4-(ethyl-2,3-dioxo-1-piperazinocarbonylamino)phenylacetamido] penicillanic acid with a solution of a reagent selected from the group consisting of sodium hydroxide, sodium carboxylates and sodium alcoholates in suitable organic solvents or organic solvents mixtures, followed by the separation by precipitation of the resulting sodium salt.
By maintaining the reagents in solution as indicated above, the process of the invention can be carried out according to various operating procedures.
According to a first embodiment of the invention, the solutions of the above mentioned penicillanic acid and of the above mentioned basic reagent chosen from sodium hydroxide, sodium carboxylates- and sodium alcoholates can be prepared in a non-sterile environment, then both solutions are subjected to sterilising filtration, and the sodium salt is precipitated in a sterile environment.
According to a second embodiment of the present process the solution of the basic reagent and the solution of the salified acid are prepared in a non-sterile environment; both solutions are then subjected to sterilising filtration, and the sodium salt is precipitated in a sterile environment, possibly by addition of a suitably sterilised non-solvent.
According to a third embodiment of the present process a sodium salt solution of the acid is prepared in a non-sterile environment; the solution is then sterilised, and the sodium salt is precipitated in a sterile environment by addition of a non-solvent previously subjected to sterilising filtration.
By operating according to the first embodiment of the invention mentioned above, the acid solution is obtained in a concentration ranging from 2% to 10% by wt. in respect of the total volume of the acid solution, and the basic solution in a concentration comprised between 2% and 10% by wt. in respect of the total volume of the basic solution.
In the second embodiment of the invention mentioned above, a basic solution having a concentration comprised between 2% and 10% by wt. in respect of the total volume of the basic solution is used, and a solution of the acid pre-salified with an organic base (the concentration of salt in this solution is up to 50%, and preferably comprised between 30 and 50% by wt. in respect of the total volume of this solution).
In the third embodiment of the invention mentioned above, a sodium salt solution of the acid is used in a concentration up to 20%, and preferably comprised between 10 and 20% by wt. in respect of the total volume of this solution.
It is a further subject of the invention the crystalline sodium salt of 6[D-(xe2x88x92)xcex14-(ethyl-2,3-dioxo-1-piperazinocarbonylamino)phenylacetamido] penicillanic acid in the monohydrated form.
The characteristics and advantages of the process according to the present invention will be apparent from the detailed description that follows.